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Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm

Romain Bourcier 1, 2 Solena Le Scouarnec 2 Stephanie Bonnaud 2, 1 Matilde Karakachoff 2, 1 Emmanuelle Bourcereau 1 Sandrine Heurtebise-Chrétien 2 Céline Menguy 2 Christian Dina 2, 1 Floriane Simonet 2, 1 Alexis Moles 1 Cédric Lenoble 1 Pierre Lindenbaum 2 Stéphanie Chatel 2, 1 Bertrand Isidor 1 Emmanuel Génin 3 Jean-François Deleuze 4 Jean-Jacques Schott 2, 1 Hervé Le Marec 2, 1 Gervaise Loirand 2 Hubert Desal 1, 2 Richard Redon 2, 1 Benjamin Daumas-Duport 1 Jérôme Connault 1 Pierre Lebranchu 5 Thierry Le Tourneau 2, 1 Pierre Viarouge Chrisanthi Papagiannaki Michel Piotin 6 Hocine Redjem 6 Mikael Mazighi 7 Jean-Philippe Desilles Olivier Naggara 8 Denis Trystram Myriam Edjlali-Goujon Christine Rodriguez Waghi Ben Hassen Suzanna Saleme Charbel Mounayer 9, 10 Olivier Levrier Pierre Aguettaz Xavier Combaz Anne Null Pasco Emeline Berthier Marc Bintner 11 Marc Molho Pascale Gauthier 12 Cyril Chivot Vincent Costalat Cyril Darganzil Alain Bonafé Anne Christine Januel 13 Caterina Michelozzi Christophe Cognard 14 Fabrice Bonneville 15 Philippe Tall Jean Darcourt Alessandra Biondi Cristina Iosif Elisa Pomero Jean-Christophe Ferré Jean Yves Gauvrit 16 François Eugène 17 Hélène Raoult Jean-Christophe Gentric Julien Ognard René Anxionnat 18, 19 Serge Bracard 18, 19 Anne Laure Derelle 20 Romain Tonnelet 21 Laurent Spelle Léon Ikka Robert Fahed 22 Aymeric Rouchaud Augustin Ozanne 23 Jildaz Caroff Nidal Ben Achour Jacques Moret Emmanuel Chabert Jérôme Berge Gaultier Marnat Xavier Barreau 24 Florent Gariel Frédéric Clarençon Mohammed Aggour Fréderic Ricolfi 25 Adrien Chavent 26 Pierre Thouant 27 Pablo Lebidinsky Brivael Lemogne Denis Herbreteau 28 Richard Bibi Laurent Pierot 29 Sébastien Soize Marc Antoine Labeyrie Christophe Vandendries Emmanuel Houdart 30 Appoline Kazemi Xavier Leclerc 31 Jean Pierre Pruvo Sophie Gallas Stéphane Velasco 
26 Registre Dijonnais des Accidents Vasculaires Cérébraux (AVC) - Dijon Stroke Registry
CEP - Centre d'épidémiologie des populations, CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
Abstract : Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)—which encodes a circulating pro-angiogenic factor mainly secreted from the liver—shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
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Romain Bourcier, Solena Le Scouarnec, Stephanie Bonnaud, Matilde Karakachoff, Emmanuelle Bourcereau, et al.. Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm. American Journal of Human Genetics, Elsevier (Cell Press), 2018, 102 (1), pp.133 - 141. ⟨10.1016/j.ajhg.2017.12.006⟩. ⟨hal-01808225⟩



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